Infectious diseases caused by bacteria and fungi affect millions of people worldwide, and in US alone cause a disease burden of more than $20 billion annually. Concerted and systemic programs to discover and develop new antibiotics and antifungals have been driven to a considerable extent by the development of resistance by these organisms to the drugs commonly used against them. However, due to the indiscriminate use of antibiotics resistance to even relatively new antibiotics such as vancomycin and methicillin are already reported in Enteroccocci and Staphylococci respectively. According to the Pharmaceutical Research and Manufacturers of America (PhRMA) there were 27 antibiotics and 12 antifungals under development in 1998 against bacterial and fungal infections in all stages of clinical development. At present, about 100 or so antibiotics are in the clinic. A key challenge to the antibiotic industry is that constant innovation is necessary not only because of resistance, but also because of side effects. Use of erythromycin a well-known macrolide antibiotic used as an alternative to patients, who are allergic to penicillins, exhibit strong gastrointestinal problems and also interact with the liver drug metabolizing enzymes. However, derivatives of erythromycin named azithromycin, dirithromycin are devoid of these problems. So, it is often possible to develop multiple analogs of successful antibiotics that achieve the same results with less adverse side effects. On the other hand these devices may increase the cost of chemotherapy. The clinical situation is much more complicated in cases where the chemotherapy has to be sustained for a longer duration (6-8 months) such as in antituberculosis therapy. The front-line antitubercular drugs rifampicin and isoniazid exhibit significant toxicity in mammalian systems. Gastric irritation, hepatitis, is some of the major side effects of nifampicin whereas, peripheral neuritis, anorexia, nausea, jaundice are associated with higher doses of isoniazid22. Under such situations to reduce the drug associated toxicity bioactivity enhancers (Bioenhancers) can be employed.
Bioenhancers are molecules, which do not possess drug activity of their own but promote and augment the biological activity or bioavailability or the uptake of drugs in combination therapy. Natural products especially from plant sources have played an important role in drug development of communicable diseases. Either the isolated plant biomolecules or its semi synthetic derivatives have provided useful clues in the production of medicines. According to WHO nearly 80% of the world's population relies on herbal medicines as primary health care. Synergism in which the action of one biomolecule is enhanced by another unrelated chemical has been the hallmark of herbal drugs. For instance, berberine and antimicrobial alkaloid isolated from Berberis fremontii has very weak antimicrobial activity in solution. However, in combination with other compound 5-Methoxy hydnocarpin (5-MHC) the antimicrobial activity of berberine is increased by 200 folds against Staphylococcus aurues23. Another interesting observation is the combination of piperine isolated from Piper nigrum with essential drugs, such as antibiotics, antihypertensive and antiepileptics as well as nutrients24, phenytoin25, pentobarbitone26, theophylline27 leading to ‘dose economy’ due to enhanced uptake, higher blood concentration and drug available for long duration in the body (U.S. Pat. No. 5,536,506; U.S. Pat. Nos. 5,616,593 and 5,972,382). Piperine has also been added in multi-drug formulations for the treatment of tuberculosis and leprosy. A formulation containing rifampicin, pyrazinamide and isoniazid has been tested in human volunteers (Indian Patent No. 1232/DEL/89). For most drugs, the comparative levels and peak concentration of the drugs in the presence of piperine were higher. We have recently demonstrated the bioenhancer activity of cow-urine distillate in a composition containing antibiotics and anticancer agents (U.S. Pat. No. 6,410,059). Thus, bioavailability enhancement helps to lower dosage levels and shorten the treatment course.